Indoloquinazolinones

ABSTRACT

The invention provides compounds of formula (I) wherein R is as defined in the description, and the preparation thereof. The compounds of formula (I) are useful as pharmaceuticals, for use in the treatment of any state associated with high levels of activeted PARP.

This application is a 371 of International Application PCT/EP 01/108192,filed Jul. 16, 2001.

The present invention relates to novel indoloquinazolinones, theirpreparation, their use as pharmaceuticals and pharmaceuticalcompositions containing them.

More particularly, the invention provides a compound of formula I

wherein

-   -   either R is —(CH₂)_(n)—X, wherein n is 1, 2 or 3 and X is        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₂₋₇)alkenyl, (C₂₋₇)alkynyl,        carboxy, (C₁₋₄)alkoxycarbonyl, cyano, tetrazolyl,        (C₃₋₇)cycloalkylamino or imidazolyl(C₁₋₄)alkylamino,    -   or R is —CH₂CON(R₁)R₂, wherein R₁ and R₂, independently, are        hydrogen, hydroxy, (C₁₋₄)alkyl, benzyl,        di(C₁₋₄)alkylamino(C₁₋₄)alkyl, (C₂₋₇)alkenyl, (C₂₋₇)alkynyl,        hydroxy(C₁₋₄)alkyl, dihydroxy (C₁₋₄)alkyl, cyanoalkyl,        carbamoylalkyl, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl(C₁₋₄)alkyl,        2-oxo-3-tetrahydrofuryl, (C₁₋₄)alkoxy(C₁₋₄)alkyl,        (C₁₋₄)alkoxycarbonyl (C₃₋₇)cycloalkyl, naphthylamino(C₁₋₄)alkyl,        imidazolylamino(C₁₋₄)alkyl, morpholinyl(C₁₋₄)alkyl,        pyrrolidinyl(C₁₋₄)alkyl, piperidinyl(C₁₋₄)alkyl or        (C₃₋₇)cycloalkylamino(C₁₋₄)alkyl, or R₁ and R₂, together with        the nitrogen atom to which they are attached, form a morpholino,        (C₁₋₄)alkyl-piperazinyl, hydroxy(C₁₋₄)alkyl-piperazinyl,        piperidinyl, pyrrolidinyl or        p-chlorophenyl(C₁₋₄)alkyl-piperazinyl, in free base or acid        addition salt form.

In a further aspect, the invention provides a process for the productionof the compounds of formula I and their salts, comprising the step ofreacting a compound of formula II

wherein R is as defined above, with sodium methoxide, and recovering theresulting compound in free base or acid addition salt form.

The reaction can be effected according to known methods, for example asdescribed in Example 1.

Compounds of formula I obtained according to the above process can beconverted into further compounds of formula I using conventionalprocedures, e.g. as described in Example 19 (hydrolysis of esters toacids), in Example 22 (tetrazole formation from nitrites), in Examples25-60 (amide formation from acids), in Example 61 (reduction of estersto alcohols), in Examples 64 and 65 (reduction of nitriles to primaryamines), in Example 66 (mesylation of alcohols and formation of sec.amines) or in Example 69 (formation of tert. amines).

Working up the reaction mixtures and purification of the compounds thusobtained may be carried out in accordance to known procedures.

Acid addition salts may be produced from the free bases in known manner,and vice-versa. Suitable acid addition salts for use in accordance withthe present invention include for example the hydrochloride.

The starting compounds of formula II may be produced by reacting10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carbontrile with potassiumtert.-butylate, and reacting the so obtained11-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-10-carbonitrile with acompound of formula III

wherein R is as defined above and Hal is halogen, preferably iodine orbromine.

The so obtained compound of formula II is preferably reacted in situinto the compound of formula I, for example as described in Example 1.

The starting material10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carbonitrile and thecompounds of formula III are known or may be produced in analogousmanner to known procedures.

Compounds of formula I and their pharmaceutically acceptable acidaddition salts, hereinafter referred to as agents of the invention,exhibit valuable pharmacological properties when tested in vitro and inanimals, and are therefore useful as pharmaceuticals.

In particular the agents of the invention inhibit the nucleic enzymepoly (adenosine 5′-diphospho-ribose) polymerase [“poly (ADP-ribose)polymerase” or PARP] as determined in in vitro assays [see for exampleI. U. Schraufstatter et al., J. Clin. Invest. 77, 1312-1320 (1986)]where they exhibit inhibition at concentrations of about 1 nM to about 1μM.

The agents of the invention are therefore useful as PARP inhibitors toprevent and/or treat tissue damage resulting from cell damage or deathdue to necrosis or apoptosis; neural tissue damage resulting fromischemia and reperfusion injury; neurological disorders andneurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, multiple sclerosis, bacterial or viral meningitis, Huntington'sdisease or amyotrophic lateral sclerosis; to prevent or treat vascularstroke; to treat or prevent cardiovascular disorders e.g. myocardialinfarction, unstable angina, cardiac arrest during cardiopulmonarybypass or other related types of myocardial ischemic-reperfusion injury;to treat or prevent ischemic-reperfusion injury in other organs, e.g.skeletal muscle, kidney etc.; to treat other conditions and/or disorderssuch as age-related macular degeneration, AIDS and other immunesenescence diseases, arthritis, atherosclerosis, cachexia, cancer,degenerative diseases of skeletal muscle involving replicativesenescence, diabetes, head trauma, spinal cord injury, immunesenescence, inflammatory bowel disorders (such as colitis and Crohn'sdisease), muscular dystrophy, osteoarthritis, osteoporosis, chronic andacute pain (such as neuropathic pain), renal failure, retinal ischemia,septic shock (such as endotoxic shock), and skin aging; to extend thelifespan and proliferative capacity of cells; to alter gene expressionof senescent cells; or to radiosensitize hypoxic tumor cells.

The cardioprotective activity of the agents of the invention isconfirmed in vivo e.g. in a model of pentobarbital-anesthetized rabbitmyocardial infarction where the infarct size is reduced uponadministration of about 1 to about 100 μmol/kg [For the model, see forexample Ytrehus K. et al., Am. J. Physiol 267 (Heart Circ. Physiol. 36):H2383-2390, 1994 and Haessler R. et al., Cardiov. Res. 28: 1574-1580,1994; for the cardioprotective effect of PARP inhibitors as evidenced inthis model, see for example Thiemermann C. et al., Proc. Natl. Acad.Sci. USA 94: 679-683, 1997].

For the above-mentioned indications, the appropriate dosage will ofcourse vary depending upon, for example, the compound employed, thehost, the mode of administration and the nature and severity of thecondition being treated. However, in general, satisfactory results inanimals are indicated to be obtained at a daily dosage of from about 0.1to about 500, preferably from about 0.5 to about 100 mg/kg animal bodyweight. In larger mammals, for example humans, an indicated daily dosageis in the range from about 1 to about 500, preferably from about 1 toabout 300 mg of an agent of the invention, conveniently administered,for example, in divided doses up to four times a day or in sustainedrelease form.

The agent of the invention may be administered by any conventionalroute, in particular enterally, preferably orally, for example in theform of tablets or capsules, or parenterally, for example in the form ofinjectable solutions or suspensions.

In accordance with the foregoing, the present invention also provides anagent of the invention, for use as a pharmaceutical, e.g. for thetreatment of diseases indicated above.

The present invention furthermore provides a pharmaceutical compositioncomprising an agent of the invention in association with at least onepharmaceutical carrier or diluent. Such compositions may be manufacturedin conventional manner. Unit dosage forms contain, for example, fromabout 0.25 to about 150, preferably from 0.25 to about 25 mg of acompound according to the invention.

Moreover the present invention provides the use of an agent of theinvention, for the manufacture of a medicament for the treatment of anycondition mentioned above.

In still a further aspect the present invention provides a method forthe treatment of any condition mentioned above, in a subject in need ofsuch treatment, which comprises administering to such subject atherapeutically effective amount of an agent of the invention.

The preferred compound of formula I is the7-(1H-tetrazole-5-ylmethyl)-6H-indolol[1,2-a]quinazoline-5-one (compoundof Example 22). This compound is a potent inhibitor of PARP in vitro(IC₅₀=12 nM). In the above-mentioned pentobarbital-anesthetized rabbitmyocardial infarction model, it dose-dependently reduces infarct sizewhen administered as a single injection at 3-70 μmol/kg i.v. (whichcorresponds to 0.95-22.1 mg/kg i.v. of the base) five minutes beforereperfusion (60% reduction at the highest dose tested).

The following examples illustrate the invention.

EXAMPLE 1 7-Ethyl-6H-indolo[1,2-a]quinazoline-5-one

Solid potassium tert.-butylate (62.3 g, 544 mmole) is added in fourportions to a solution of10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carbonitrile (75 g, 320mmole) in 2.5 l of 1,2-dichloroethane at r.t. within 2 h. Thereafter amixture of acetic acid (32.2 ml) and 300 ml ice-cold water is slowlyadded. The resulting suspension is stirred for 10 min., cyclohexan (650ml) is added and stirring is continued for 1 h at 0° C. The precipitateis collected by filtration, washed with water (300 ml) and cyclohexane(300 ml). The so obtained11-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-10-carbonitrile (pale-yellowcrystals) is recrystallized from 2.5 l boiling EtOH upon concentrationto 1.2 l and slow cooling. m.p.: 195-197° C.; ES-MS(+): 235 (M+1);¹H-NMR (CDCl₃, 200 MHz): 4.90 (s, 1H); 6.81 (s br, 1H); 6.95-7.18 (m,3H); 7.29-7.35 (m, 2H); 7.49 (td, 1H); 7.65 (dd, 1H); 8.01 (dd, 1H).

A mixture of 11-oxo-10,11-dihydro-5H-dibenzo[b,f]azepine-10-carbonitrile(500 mg, 2.13 mmol), potassium carbonate (359 mg, 2.6 mmole) and ethyliodide (0.202 ml, 2.5 mmole) in 4 ml DMF is stirred at r.t. for 18 h.

After removal of solid particles, methanolic sodium methoxide solution(2 ml, 5.4 M) is added, followed by heating at 65° C. for 5 h. Themixture is poured into ice-water (40 ml) containing 1 ml AcOH, extractedwith dichloromethane (3×40 ml), and the organic layers are dried usingMgSO₄, then evaporated. 7-Ethyl-6H-indolo[1,2a]quinazoline-5-one (323.3mg, 58%) crystallizes spontaneously from EtOH as pale-yellow platelets.m.p.: 245-260° C.; ES-MS(+): 263 (M+1); ¹H-NMR (d₆-DMSO, 300 MHz): 1.12(t, 3H); 2.81 (q, 2H); 7.19-7.29 (m, 3H); 7.39 (t, 1H); 7.58 (d, 1H);7.84 (t, 1H); 8.19 (d, 1H); 8.27 (d, 1H); 8.41 (d, 1H); 11.55 (s br,1H).

The following compounds of formula I are prepared analogously to Example1:

Ex R Characterization 2 CH₃ yellow crystals. m.p.: >260° C. ES-MS(+):248 (M + 1) 3 CH₂CH₂CH₃ pale-yellow crystals. m.p.: 245-250° C.ES-MS(+): 277 (M + 1) 4 CH₂CH₂CH₂CH₃ pale-yellow crystals. m.p.:247-249° C. ES-MS(+): 291 (M + 1) 5 CH(CH₃)₂ yellow crystals. m.p.:238-240° C. ES-MS(+): 277 (M + 1) 6 CH₂CH(CH₃)₂ yellow crystals. m.p.:260-268° C. ES-MS(+): 291 (M + 1) 7 CH(CH₃)CH₂CH₃ pale-yellow crystals.m.p.: 207-220° C. ES-MS(+): 291 (M + 1) 8 CH₂CH═CH₂ pale-yellowcrystals. m.p.: 247-259° C (dec.) ES-MS(+): 275 (M + 1) 9 CH₂CH₂C₆H₅yellow crystals. m.p.: 292-302° C. ES-MS(+): 339 (M + 1) 10 CH₂C₆H₅yellow crystals. m.p.: 241 -249° C. ES-MS(+): 325 (M + 1) 11 CH₂C≡CHyellow crystals. m.p.: 208-210° C. ES-MS(+): 273 (M + 1) 12 CH₂COOCH₃yellow crystals. m.p.: > 220° C. (dec.). ES-MS(+): 306 (M + 1) 13CH₂CH₂COOCH₃ yellow crystals. m.p.: 269-270° C. ES-MS(+): 321 (M + 1) 14CH₂CH₂CH₂COOCH₃ yellow crystals. m.p.: 253-254° C. ES-MS(+): 335 (M + 1)15 CH₂CN off-white solid. m.p.: 283-290° C. (dec.). ES-MS(+): 274(M + 1) 16 CH₂CH₂CN yellow crystals. m.p.: 285-299° C (dec.). ES-MS(+):288 (M + 1) 17 CH₂CH₂CH₂CN yellow crystals. m.p.: dec. >230° C.ES-MS(+): 302 (M + 1) 18 CH₂CH₂OCH₃ yellow crystals, obtained afteralkylation reaction with 1-bromo-2-chloro-ethane. m.p.: 172-182° C.ES-MS(+): 293 (M + 1)

EXAMPLE 19 (5-Oxo-5,6-dihydro-indolo[1,2-a]quinazoline-7-yl) acetic acid

A suspension of (5-Oxo-5,6-dihydro-indolo[1,2a]quinazoline-7-yl) methylacetate (5.0 g, 16.32 mmole, Example 12) in DMSO (50 ml) is treated with1N aqueous sodium hydorixyde solution. The mixture is diluted with water(150 ml) and the free acid (yellow crystals) brought to precipitation byaddition of acetic acid (20 ml). m.p.: dec.>190° C.; ES-MS(+): 291(M+1); ¹H-NMR (d₆-DMSO, 200 MHz): 3.83 (s, 2H); 7.21-7.30 (m, 2H);7.35-7.52 (m, 2H); 7.85 (td, 1H); 8.15-8.30 (m, 2H); 8.42 (d, 1H).

The following compounds of formula I are prepared analogously to Example19:

Ex R Characterization 20 CH₂CH₂COOH yellow crystals. m.p.: 288-290° C.ES-MS(−): 305 (M − 1) 21 CH₂CH₂CH₂COOH yellow crystals. m.p.: 272-276°C. ES-MS(−): 319 (M − 1)

EXAMPLE 22 7-(1H-Tetrazole-5-ylmethyl)-6H-indolo[1,2-a]quinazoline-5-one

A solution of(5-oxo-5,6-dihydro-indolo[1,2a]quinazoline-7-yl)-acetonitrile (1.2 g,4.39 mmole) (Example 15), sodium azide (856.4 mg, 13.2 mmole) andtriethylamine hydrochloride (907 mg, 6.6 mmole) in1-methyl-2-pyrrolidone (30 ml) is heated at 100° C. for 18 h. Themixture is poured into ice-water (500 ml), acidified to pH 1 with 2Nhydrochloric acid and stirred for 15 min. The product is extracted withethyl acetate, the organic layers are washed with water and brine, driedusing MgSO₄, filtered, and evaporated. The remaining solid isprecipitated from MeOH with hexane giving a brownish solid. m.p.:262-265° C.; ES-MS(−): 315 (M−1); ¹H-NMR (d₆-DMSO, 300 MHz): 4.52 (s,2H); 7.16-7.30 (m, 2H); 7.38 (t, 1H); 7.52-7.58 (m, 1H); 7.85 (t, 1H);8.15-8.30 (m, 2H); 8.42 (d, 1H).

The following compounds of formula I are prepared analogously to Example22:

Ex R Characterization 23 CH₂CH₂-tetrazole pale off-white crystals. m.p.:289-291° C. ES-MS(−): 329 (M − 1) 24 CH₂CH₂CH₂-tetrazole yellowcrystals. m.p.: 256-260° C. ES-MS(−): 343 (M − 1)

EXAMPLES 25-60 Parallel synthesis of7-acetamido-6H-indolo[1,2-a]quinazoline-5-one derivatives

In a parallel synthesis set-up on a 0.1 mmol scale(5-Oxo-5,6-dihydro-indolo[1,2a]quinazoline-7-yl) acetic acid (Example19) is pre-activated withN-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride (EDC) and1-hydroxy-benzotriazole (HOBt) in 1-methyl-2-pyrrolidone, then dividedinto 25 parts and added to primary or secondary amines. Triethylamine isused as an additional base in order to trap HCl from EDC and in case thehydrochloride salts of the amines are used. (Molar ratios: acid: 0.1mmol; EDC, HOBt: 2 eq.; Et₃N: 4 eq. amine: 1.0 eq.). After 18 h ofshaking, the reaction mixtures are filtered (0.45μ syringe filters) anddirectly injected into a preparative HPLC (reverse phase C-18). Thelargest peaks at 254 nm are collected, the solvents evaporated and theproduct analyzed by electrospray-MS. In most cases, the product directlycrystallizes during evaporation of the solvents. The solid products aredried in vacuo at 80° C. for 18 h.

Ex NR1R2 Characterization 25 morpholino yellow crystals. ES-MS(+): 362(M+1) 26 NHEt yellow crystals. ES-MS(+): 320 (M+1) 27 NH₂ yellowcrystals. ES-MS(+): 292 (M+1) 28 4-Me-1-piperazinyl yellow crystals.ES-MS(+): 375 (M+1) 29 1-piperidinyl yellow crystals. ES-MS(+): 360(M+1) 30 1-pyrrolidinyl yellow crystals. ES-MS(+): 346 (M+1) 31 N(CH₃)₂yellow crystals. ES-MS(+): 320 (M+1) 32 N-Me-benzyl yellow crystals.ES-MS(+): 396 (M+l) 33 NHCH₂CH₂NMe₂ yellow crystals. m.p.: 236-240° C.(dec.); ES-MS(+): 363 (M+1) 34 NHCH₃ yellow crystals. m.p.: >325° C.(dec.); ES-MS(+): 305 (M+1) 35 NH-propargyl yellow crystals. ES-MS(+):330 (M+1) 36 NH-allyl yellow crystals. ES-MS(+): 332 (M+1) 37NH-n-propyl yellow crystals. ES-MS(+): 334 (M+1) 38 N-Me-propargylyellow crystals. ES-MS(+): 344 (M+1) 39 NHCH₂CH₂OH yellow crystals.m.p.: 274-280° C. (dec.); ES-MS(+): 336 (M+1) 40 NHCH₂CH₂CH₂OH yellowcrystals. m.p.: 271-280° C. (dec.); ES-MS(+): 350 (M+1) 41 NHCH₂CNyellow crystals. ES-MS(+): 331 (M+1) 42 NHCH₂CONH₂ yellow crystals.m.p.: 297-299° C. (dec.); ES-MS(+): 349 (M+1) 43 NHCH₂-cyclopropylyellow crystals. ES-MS(+): 346 (M+1) 44 NHCH₂CH(OH)— yellow solid. m.p.:297-299° C. (dec.); CH₂OH ES-MS(+): 366 (M+1) 45

yellow crystals. m.p.: 276-281° C. (dec.); ES-MS(+): 376 (M+1) 46NH-cyclopropyl yellow solid. m.p.: 297-302° C. (dec.); ES-MS(+): 332(M+1) 47 NHCH₂CH₂OCH₃ yellow solid. m.p.: 262-273° C. (dec.); ES-MS(+):350 (M+1) 48 4-CH₂CH₂OH-1- yellow solid. ES-MS(+): 405 (M+1) piperazinyl49

yellow crystals. ES-MS(+): 389 (M+1) 50 p-Cl-phenyl- yellow solid.ES-MS(+): 500 (M+1) piperazinyl-4-ethyl 51 NHOH yellow powder. ES-MS(+):306 (M+1) 52 NHCH₂CH₂NH-2- brown solid. ES-MS(+): 461 (M+1) naphthyl 53NHCH₂CH₂NH-4- brown solid. ES-MS(+): 386 (M+1) imidazolyl 54 NHCH₂CH₂-brown solid. ES-MS(+): 405 (M+1) morpholino 55 NHCH₂CH₂-1- brown solid.ES-MS(+): 389 (M+1) pyrrolidinyl 56 NHCH₂CH₂-1- brown solid. ES-MS(+):403 (M+1) piperidinyl 57 NHCH₂CH₂CH₂- brown solid. ES-MS(+): 419 (M+1)morpholino 58 NHCH₂-4-piperidinyl green solid. ES-MS(+): 389 (M+1) 59NHCH₂CH₂CH₂NH- brown solid. ES-MS(+): 431 (M+1) cyclohexyl 60NHCH₂CH₂CH₂NMe₂ brown solid. ES-MS(+): 377 (M+1)

EXAMPLE 61 7-(2-Hydroxy-ethyl)-6H-indolo[1,2-a]quinazoline-5-one

A THF (25 ml) solution of lithium borohydride (0.62 g, 28.56 mmole) isadded dropwise to a suspension of(5-oxo-5,6-dihydro-indolo[1,2-a]quinazoline-7-yl) methyl acetate (2.5 g,8.16 mmol) (Example 12) in THF (40 ml) at r.t. The reaction mixture isheated at 75° C. for 18 h. Then ethanol (100 ml) and water (20 ml) areadded after cooling to 10° C. After 15 min. the mixture is chilled to 0°C. and acidified (pH 7) with 2N hydrochloric acid, giving a thick yellowsuspension. The product (1.6 g, 71%) is collected by filtration, washedwith water and ethanol and dried in vacuo at 60° C. m.p.: 248-252° C.ES-MS(+): 279 (M+1); ¹H-NMR (d₆-DMSO, 200 MHz): 1.15 (s br, 1H); 2.90(t, 2H); 3.60 (t, 2H); 7.15-7.30 (m, 2H); 7.38 (t, 1H); 7.53-7.61 (m,1H); 7.85 (td, 1H); 8.13-8.31 (m, 2H); 8.43 (d, 1H).

The following compounds of formula I are prepared analogously to Example61:

Ex R Characterization 62 CH₂CH₂CH₂OH yellow crystals. m.p.: 255-257° C.ES-MS(+): 293 (M + 1) 63 CH₂CH₂CH₂CH₂OH yellow crystals. m.p.: 259-264°C. ES-MS(+): 307 (M + 1)

EXAMPLE 64 7-(2-Amino-ethyl)-6H-indolo[1,2-a]quinazoline-5-one

(5-Oxo-5,6-dihydro-indolo[1,2-a]quinazoline-7-yl)-acetonitrile (0.5 g,1.83 mmol) (example 15) is dissolved in DMF (25 ml) and MeOH with 10%NH₃ (25 ml) and catalytically hydrogenolized with Raney-Nickel (0.2 g)in ethanol at 50° C. for 9 h. The catalyst is removed by filtration. Theproduct spontaneously crystallizes from the filtrate giving 0.23 mg(46%) slightly greenish crystals. m.p.: >300° C. ES-MS(+): 278 (M+1).

EXAMPLE 65 7-(2-Amino-butyl)-6H-indolo[1,2-a]quinazoline-5-one

This compound is prepared in analogy to Example 64 using(5-Oxo-5,6-dihydro-indolo[1,2-a]quinazoline-7-yl)-butyronitril (Example17) as starting material. m.p.: 165-195° C. (dec.). ES-MS(+): 306 (M+1).

EXAMPLE 667-[2-(2-Morpholin-4-yl-ethylamino)-ethyl]-6H-indolo[1,2-a]quinazoline-5-onedi-hydrochloride salt

2-(5-Oxo-5,6-dihydro-indolo[1,2-a]quinazoline-7-yl)-ethylmethanesulfonate is prepared from7-(2-hydroxy-ethyl)-6H-indolo[1,2a]quinazoline-5-one in pyridine at 0°C. upon addition of methane sulfochloride. To a solution of theresulting methanesulfonate (0.2 g, 0.56 mmol) in 1-methyl-2-pyrrolidone(2 ml), 4-(2-aminoethyl)morpholine (0.11 ml, 0.84 mmole) is added atr.t., followed by heating at 65° C. for 4 h. After cooling, water (15ml) is added and the product extracted with dichloromethane. The organiclayers are washed with water and brine, dried with MgSO₄, and thesolvent is evaporated. The resulting oil is dissolved in methanol. 1NHCl in ethanol addition leads to crystallization of the di-hydrochloridesalt. m.p.: 196-198° C. ES-MS(+): 391 (M+1).

The following compounds of formula I are prepared analogously to Example66:

Ex R Characterization 67 CH₂CH₂NH- brown crystals. m.p.: 190-192° C.ES-MS(+): 318 (M + 1) cyclopropyl, hydrochloride 68 CH₂CH₂NHCH₂CH₂-brown crystals. m.p.: 88-92° C. ES-MS(+): 372 (M + 1) imidazole-4-yl(free base)

EXAMPLE 697-[2-(2-Oxo-pyrrolidine-1-yl)-ethyl]-6H-indolo[1,2-a]quinazoline-5-one

Pyrrolidone (0.131 ml, 1.71 mmole) is added dropwise to sodium hydride(0.048 g, 1.11 mmole, 55% oily suspension) in DMF (1 ml) at 0° C.followed by addition of2-(5-oxo-5,6-dihydro-indolo[1,2-.a.]quinazoline-7-yl)-ethylmethanesulfonate (0.304 g, 0.85 mmole, prepared as described in example67) and stirring at r.t. overnight. Ice-water (80 ml) is added and themixture extracted with tert.-butyl-methyl ether. The organic layers arewashed with water and brine, dried over MgSO₄, filtered, and the solventis evaporated. The remainder is purified by preparative reverse-phase(C-18) HPLC. m.p.: 154-155° C. ES-MS(+): 347 (M+1).

1. A compound of formula

wherein either R is —(CH₂)_(n)—X, wherein n is 1, 2 or 3 and X is(C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₂₋₇)alkenyl, carboxy, (C₁₋₄)alkoxycarbonyl,cyano, tetrazolyl, (C₃₋₇)cycloalkylamino or imidazolyl(C₁₋₄)alkylamino,or R is —CH₂CON(R₁)R₂, wherein R₁ and R₂, independently, are hydrogen,hydroxy, (C₁₋₄)alkyl, benzyl, di(C₁₋₄)alkylamino(C₁₋₄)alkyl,(C₂₋₇)alkenyl, (C₂₋₇)alkynyl, hydroxy(C₁₋₄)alkyl, dihydroxy (C₁₋₄)alkyl,cyanoalkyl, carbamoylalkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₄)alkyl, 2-oxo-3-tetrahydrofuryl,(C₁₋₄)alkoxy(C₁₋₄)alkyl, (C₁₋₄)alkoxycarbonyl (C₃₋₇)cycloalkyl,naphthylamino(C₁₋₄)alkyl, imidazolylamino(C₁₋₄)alkyl,morpholinyl(C₁₋₄)alkyl, pyrrolidinyl(C₁₋₄)alkyl, piperidinyl(C₁₋₄)alkylor (C₃₋₇)cycloalkylamino(C₁₋₄)alkyl, or R₁ and R₂, together with thenitrogen atom to which they are attached, form a morpholino,(C₁₋₄)alkylpiperazinyl, hydroxy(C₁₋₄)alkyl-piperazinyl, piperidinyl,pyrrolidinyl or p-chlorophenyl(C₁₋₄)alkyl-piperazinyl, in free base oracid addition salt form. 2.7-(1H-Tetrazole-5-ylmethyl)-6H-indolo[1,2-a]quinazoline-5-one in freebase or acid addition salt form.
 3. A pharmaceutical compositioncomprising a compound of claim 1 in free base or pharmaceuticallyacceptable acid addition salt form, in association with a pharmaceuticalcarrier or diluent.
 4. A process for the preparation of a compound offormula I as defined in claim 1, or a salt thereof, comprising the stepof reacting a compound of formula II

wherein R is as defined in claim 1, with sodium methoxide, andrecovering the resulting compound in free base of acid addition saltform.